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Breakthrough in preclinical model for human cancer may lead to new
drug development

23 April 2009

AVEO Pharmaceuticals, Inc., a biopharmaceutical company leveraging
breakthrough discoveries in cancer biology to discover, develop and
commercialize targeted oncology therapies, has announced findings from
its novel human-in-mouse (HIM) cancer model system, in which AVEO
successfully created invasive human tumours from primary human breast
tissue that develop over time in mice and mimic human tumour behaviours
and response.

The findings were published in the Early Edition of the Proceedings
of the National Academy of Sciences.

More than 95% of oncology drugs entering the clinic fail, due in
large part to the lack of predictive animal models in the preclinical
development phases. AVEO scientists have developed a sophisticated
cancer biology platform that provides models of human cancer more
relevant than traditional mouse models known as xenografts.

In the AVEO HIM model, normal human breast tissue is engineered to
express oncogenes and is then introduced into mice where it forms human
breast tissue in the mouse mammary microenvironment. The tumours which
then develop spontaneously acquire common and distinct mutations during
tumour progression. This process results in human tumours in mice that
reflect their human counterparts in that they differ slightly from one
instance to another, exhibiting natural genetic variation akin to that
seen in patients.

“Historically, the xenograft models created to analyze how human
cancers behave have not been accurate predictors of human responses to
various therapeutic agents,” said Robert A Weinberg, PhD, member,
Whitehead Institute and professor of biology, MIT.

“In contrast, tumour development in the HIM model proceeds through
defined histological stages of hyperplasia, from ductal carcinoma in
situ (DCIS) to invasive carcinoma. Moreover, HIM tumours display
characteristic responses to a targeted therapy known to be effective in
humans, specifically Herceptin.

"This represents a big step forward in developing xenograft models
that will accurately predict patient responses to agents that are in
preclinical development. The HIM model is an exciting, experimentally
tractable human in vivo system that holds great potential for advancing
our basic understanding of cancer biology and for the discovery and
testing of targeted therapies.”

By employing a tissue recombinant system and a gene transduction
system, researchers assessed the in vivo biological consequences of
specific genetic alterations in the reconstituted breast tissue.
Introduction of different combinations of oncogenes, such as HER2, KRAS,
PI3 kinase and p53, into the tissue enabled the researchers to dissect
the contribution of each gene to human tumour formation in the model.

The authors also demonstrated the utility of the HIM models for drug
efficacy testing by treating the HER2 driven breast tumours with
different HER2 antagonists. The resulting potent inhibition of HIM tumor
growth correlates with what has been observed in the clinic.

"With the increasing knowledge of specific genetic alterations in
breast cancer, there is now a significant opportunity to correlate
activity of anticancer agents with specific genetic alterations in
tumors,” added Murray O Robinson, PhD, senior vice president, oncology
at AVEO.

“Our proprietary models provide a defined genetic context in which to
validate cancer gene candidates, determine their biological roles in
various stages of cancer progression and test targeted therapies. We
have been very encouraged by the similarity to human patients in
response to widely used breast cancer agents."

The study, entitled “Dissecting genetic requirements of human breast
tumorigenesis in a tissue transgenic model of human breast cancer in
mice” by Min Wu et al, is available online on PNAS at
www.PNAS.org.

AVEO's Proprietary Human Tissue Transgenic HIM Model

AVEO sought to generate an in vivo model of human breast cancer in
mice (HIM) by employing a unique tissue recombinant system comprised of
human breast stromal cells and epithelial organoids engineered with
defined transgenes.

Depending on the combination of transgenes employed, the
reconstituted human breast tissue developed into preneoplastic lesions
(Carcinoma In Situ or CIS) or to invasive adenocarcinomas. Importantly,
despite using the same set of genetic alterations, significant variation
in tumour phenotype was observed among tumours depending on the source
of donor organoids.

This last observation suggests that differences in the genetic makeup
individual donors may influence the development and progression of these
tissue transgenic breast tumours. Because this observed variation is
similar to what is seen across human breast cancer patients, AVEO is
generating a large number of individual tissue transgenic breast tumours
to create a population of tumours in which to explore the relationship
between this variation and response to anti-cancer agents.

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